A variety of human diseases and conditions which are manifested by cardiac abnormalities or cardiac dysfunction can lead to heart failure. Heart failure is a pathophysiological condition in which the heart fails to pump blood at a rate commensurate with the requirements of the metabolizing tissues of the body. When the heart begins to fail, physiological mechanisms for modulating the function of the heart are utilized to increase heart rate and contractility.
The most important of the mechanisms that are responsible for modulating cardiac function are the adrenergic pathways. In a normal heart, these pathways are largely responsible for allowing cardiac pumping performance to meet the circulatory demands of increased activity by rapidly increasing or decreasing cardiac function according to circulatory demands. The cellular actions of these pathways are mediated through a family of receptors, called adrenergic receptors. There are two .beta.-adrenergic receptor subtypes, .beta..sub.1 and .beta..sub.2, which, when stimulated, initiate a G-protein coupled signaling cascade, resulting in immediate stimulation of pump performance.
When the heart begins to fail, adrenergic activity is stimulated by increased sympathetic nerve activity, presynaptic facilitation of norepinephrine release and eventually, decreased neuronal norepinephrine reuptake. Increased circulating epinephrine also stimulates cardiac .beta.-adrenergic receptors, particularly in the initial phase of heart failure.
In heart failure, the immediate stimulation of pump performance by .beta.-adrenergic mechanisms is subsequently aided by two additional means of stabilizing or increasing cardiac function. These are an increase in plasma volume, which in turn increases preload, and hypertrophy of the cardiac myocytes, which results in more contractile elements. The subcellular mechanisms mediating these additional cardiac functions include both the .beta.-adrenergic receptor pathways and the .alpha..sub.1 -adrenergic receptor pathway, among other myocellular pathways.
In the failing ventricular myocardium, the exposure to elevated levels of cognate agonists causes the adrenergic receptors to undergo regulatory changes. In particular, the .beta..sub.1 -adrenergic receptor exhibits down-regulation or loss of receptor protein and may also be partially uncoupled from the signaling response. .beta..sub.2 -adrenergic receptors are not down-regulated, but are weakly uncoupled from the signaling response. The .alpha..sub.1 -adrenergic receptors are slightly up-regulated and are partially uncoupled from the signaling response. These changes in adrenergic receptor expression and signaling partially withdraw the cardiac myocyte from chronic stimulation, although some adrenergic function remains. The increased agonist exposure, however, continues to chronically stimulate the remaining adrenergic signaling function, resulting in the compromise of the modulatory effects of the adrenergic system. Therefore, the prime functional capabilities of the adrenergic system, to rapidly and substantially increase or decrease cardiac function according to demand, are compromised, while the adverse effects of chronic stimulation of cardiac function remain.
Numerous compounds have been identified and used to inhibit the functions of the .beta.-adrenergic receptors, and thus, eliminate the adverse effects of chronic myocardial stimulation through the adrenergic pathways. These compounds, often called .beta.-adrenergic antagonists or .beta.-blockers, interact with the .beta.-adrenergic receptors and thereby inhibit or prevent cellular signaling by the endogenous agonists. One .beta.-adrenergic antagonist can differ from another in a variety of ways, including by receptor subtype specificity, effect on expression of the adrenergic receptor, and effect on adrenergic receptor signaling.
Although .beta.-adrenergic antagonists are important therapeutic tools for use in patients experiencing heart failure, these drugs are often not well tolerated by patients, causing adverse side effects, such as bradycardia, myocardial depression, dyspnea and fluid retention. The characteristics which contribute to the poor tolerability (i.e., undesirable side effects) of .beta.-adrenergic antagonists are controversial and not well understood. See Kelly and Smith, in Heart Disease: A Textbook Of Cardiovascular Medicine, Chapter 16 at page 488 (5th ed., Braunwald ed., 1997).
Therefore, there is a need to develop a standardized method for screening adrenergic receptor antagonists for use in the treatment of heart failure which identifies adrenergic receptor antagonists that have good tolerability in patients.